Significant efforts are still underway in the biomedical engineering community to understand the responses of the brain and mechanisms of brain injury to traumatic insult. This understanding is required to design efficacious strategies and equipment to prevent injury. The primary mechanism of traumatic brain injury (TBI) is mechanical in origin in that rapid mechanical deformation dictates the response of neural tissue directly at the time of trauma and is believed to contribute to secondary injury leading to subsequent neurological disability. However, in vivo quantification of the tissue responses under dynamic loading conditions continues to be a significant challenge. At present, the relationship between neural tissue mechanical response and resulting injury has not been fully elucidated. The long-term goal associated with this research is to determine the tissue-specific thresholds for a range of brain injuries and to quantify the linkage between the mechanical injury and neurological outcomes. The goal of this application is to elucidate the extent of axonal damage induced by a range of mechanical insults as a function of the tissue response and to determine the mechanical thresholds for white matter injury. The central hypothesis is that traumatic axonal injury is directly induced by the synergistic effect of the principal strain and the rate of principal strain to the local tissue. To test the hypothesis and achieve the overall goal, the following three specific aims will be pursued: Specific Aim 1: To develop and validate an anatomically-based finite element model of the rat head for predicting in vivo brain injury of various severities. Specific Aim 2: To characterize the kinematics of the rat head during dynamic impact of various severities along with the quantification of the intensity and distribution of the axonal changes throughout the brain using histopathologic techniques. Specific Aim 3: To correlate the predicted biomechanical response with the axonal changes in the in vivo rat brain, thereby establishing tissue thresholds for white matter injury at varying levels of severity. The approach is innovative because it combines biomechanically-based in vivo experimental and computer models to examine and quantify the acute underlying mechanisms that lead to axonal changes. The proposed research is significant, because it is expected to result in a detailed understanding of tissue level mechanical thresholds for white matter injury, as well as stringent correlations between extent of white matter injury and tissue response. PUBLIC HEALTH RELEVANCE: Understanding these relationships will significantly improve our ability to predict brain injury using the human head finite element model. This improvement will lead to the development of revised brain injury criteria necessary for the development of efficacious strategies and equipment to prevent such injury from occurring. In addition, the threshold information is expected to provide a basis for elucidating subsequent neurological dysfunction associated with the initial tissue response, contributing to the selection of effective therapies for the treatment of brain injured patients.